Implementation of molecular diagnosis for PAH related disorders in a public Hospital

ANA CHIESA; MÉNDEZ V; MARÍA GABRIELA ROPELATO; ESNAOLA AZCOITI, MARÍA; VALLE GABRIELA; ALTUBE, MERCEDES; ENACAN ROSA; GOTTA, GABRIELA; PAULA ALEJANDRA SCAGLIA

Congreso; Reunión Anual de Biociencia 2020; 2020

Sociedad Argentina de Investigación Clínica

Introduction: Hyperphenylalaninemia (HPA) is a biochemical phenotypemainly due to variants in PAH. Its spectrum ranges from classicalphenylketonuria (PKU) to persistent benign hyperphenylalaninemia(PHPA). Genotyping has become a useful tool to either design thediet accurately or to consider other treatment options now available.Aim: to efficiently implement the molecular diagnosis for PAH relateddisorders in our patients. Methods: 27 patients (9 female) with clinicaland biochemical diagnosis of HPA were included. According totheir tolerance to phenylalanine they were classified as classic PKU(n:6), moderate (n: 8), mild (n:7) or PHPA (n:6). Six patients underwentmolecular diagnosis by NGS (TSO Illumina, NextSeq500) and21 were studied by Sanger sequencing of PAH exons and intronicflanking regions. Variants were classified according to ACMG criteriaand information available in BIOPKU database. Parents and siblingswere studied to assess segregation for all prioritized variants. Results:25 different already reported variants were found. 26 patientswere homozygous or compound heterozygous. In one patient, NGSfound only one heterozygous variant but bioinformatic CNV-analysispredicted a PAH exon 3 deletion (confirmation pending). Most frequentvariants were c.1066-11G>A (intron 10:21%), p.V388M (exon11:7,7%), p.R261Q (exon 7:7,7 %), p.R408W (exon 12:5,8%) andp.R158Q (exon 5, 5,8%). 35% of all variants found were in exon 11and its intronic regions, 17% in exon 12, 13% in exon 7, 7% in exons2 and 3, 5,5% in exons 5, 6 and 10 and 2% in exon 9. No variantswere found in exons 1, 4, 8 or 13. Conclusions: We were able tofully characterize our cohort confirming the allelic heterogeneity ofPKU patients and the prevalent occurrence of variants in 6 exons,accounting for 83% of the variants found. This suggests that PAHmolecular characterization in our media should start with these exonsand be followed by the other ones only if negative or incomplete.